Selectide technology (Lam et al., 1991) can generate large statistically complete combinatorial libraries of oligopeptides. Peptide libraries will by synthetized in the bound form - attached to the polymeric beads - or as a mixture of peptides released to the solution just before the test. The Selectide technology will be first applied to HIV-1 RNase H as an acceptor molecule. The peptide-containing beads will be identified by their ability to specifically bind the isolated domain of HIV-1 RNase H. Using several detection techniques, the binding peptides will be identified and their sequence determined. the identified peptides will be synthesized, retested for their binding and inhibitory activities, and provided for co- crystallization experiments to investigators in Project 4 of this NCDDG. Based on the structural information, modified peptides and analogues with increased binding affinities will be synthesized. A similar approach will be used and extended also to other therapeutic targets in HIV system, such as the DNA polymerase domain of HIV-1 RT (p51), nucleocapsid protein (NC) and Rev protein. We believe that the combination of the newly developed Selectide technology with structural information on ligand binding and molecular modelling can lead to the more efficient design of anti HIV drugs.